Polygenic risk and genomic signals in premature coronary artery disease

Background: Premature coronary artery disease (pCAD) is a distinct presentation of CAD. Using the All of Us (AoU) Research Program data, we compared pCAD with later-onset CAD across cardiometabolic, polygenic, and genome-wide domains. Methods: We conducted a retrospective, cross-sectional case-case analysis of All of Us Research Program (AoU) participants with established CAD. pCAD was defined as first CAD event before age 55 years in males and before age 65 in females; later-onset CAD was defined as the first CAD event at or after age threshold. Pre-index cardiometabolic measures were extracted from electronic health records and modelled with logistic regression. Using 607,719 variants, a CAD polygenic risk score (PRS) was constructed using published summary statistics and short-read whole-genome sequencing data (srWGS). Results were standardized within self-reported race groups, and evaluated overall, by race, and with a PRS x race interaction. A case-case genome-wide association study (GWAS) compared pCAD with later-onset CAD. Results: The CAD cohort included 49,919 participants, including 18,455 with pCAD and 31,464 with later-onset CAD. Participants with pCAD had higher BMI, LDL cholesterol and diastolic blood pressure, and lower HDL cholesterol, serum calcium, and systolic blood pressure. Higher BMI and LDL cholesterol were positively associated with higher odds of pCAD, whereas higher HDL cholesterol, systolic blood pressure, and serum calcium were inversely associated. PRS was associated with greater odds of pCAD in the genomic models (OR per 1-SD higher PRS, 1.14; 95% CI, 1.12?1.17; P<0.001). Analyses stratified by race showed PRS association was present among White participants but was not observed among Black participants. In the case-case GWAS, one variant reached genome-wide significance at 2q24.3 (rs13383835; OR=1.20; 95% CI, 1.13-1.27; P=5.8x10-9). A total of 137 variants met an exploratory threshold of P<1x10-5. Conclusions: Premature onset of CAD is characterized by a distinct cardiometabolic profile driven by modifiable risk factors, greater polygenic burden, and genomic signals associated with earlier disease timing. A European-derived PRS did not transfer to Black participants, who were overrepresented in pCAD. Together, these findings support pCAD as a clinically and genetically distinct presentation of CAD and highlight the need for ancestry-specific validation of genomic risk tools in diverse cohorts.